This application is one of a set of coordinated proposals submitted by a cooperating group of principal investigators. Four PIs (Spielman [group coordinator], Bell, Concannon and Risch) form the core of this grouping; they will use the same set of IDDM family DNAs obtained from the Human Biological Data Interchange (HBDI) and/or the British Diabetic Association Warren Repository to scan the genome for "genes responsible for IDDM". Drs. Spielman, Bell and Concannon will divide the labor of screening the human genome, and will share all resources, eg. DNA samples from the families, oligonucleotide primers and primer sequences, and genotype data obtained on DNA polymorphisms. These three PIs will send genotype data to Risch at Yale University, who will be responsible for data management and linkage analysis. This collaboration will allow us to carry out uniform analyses on all the markers typed by each group. In addition, it will be possible to carry out conditional analyses that take into account data at some loci such as HLA, when analyzing data on others. It is important to stress that we propose to screen the entire genome for IDDM susceptibility genes. We are not proposing to look for a locus and when we identify one stop. Rather, we are looking for ALL the regions in the genome that contribute to IDDM susceptibility, in order to define how they act together and with environmental factors to cause IDDM. Two other PIs in the cooperating group are Drs. Lernmark and Eisenbarth. Their participation will enhance the testing and confirmation of results from the core group, since their principal focus is not on the same families being studied by the "core" group. As we in the core group identify markers/regions possibly linked (or excluded from linkage) to IDDM, we will provide information to them, for confirmation in their materials. Likewise, they will provide us with information on any potential linkages that they may identify. The four principal investigators in the cooperating group (Spielman, Bell, Concannon and Risch) will coauthor all publications that come from this collaboration. The overall goal of this coordinated application is the elucidation of the mechanisms involved in IDDM onset, thereby enabling the development of specific intervention therapies and the identification of individuals at risk of development of IDDM.